Intravenous or oral cyclophosphamide, 150-250 mg/m2 (500 mg maximum), once per week with alternate-day oral prednisone, 100 mg, was given to 57 myeloma patients resistant to melphalan and prednisone (MP). Seven responses in 28 primary MP-resistant patients and ten responses in 29 secondary MP-resistant patients were observed. Previous response to MP was not a significant factor in predicting response to weekly cyclophosphamide and alternate-day prednisone. The results suggest that the regimen of weekly cyclophosphamide and alternate-day prednisone may be as effective as more aggressive regimens in the treatment of patients with myeloma who have failed MP therapy. However, a randomized trial would be required to determine the relative contributions of cyclophosphamide and prednisone to the effectiveness of this regimen.